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The majority of scientists working in the field of cancer experimental therapeutics recognize that many drugs that claim to be “specific” for one target enzyme in fact regulate to varying degrees the activities of other additional protein targets. Some of these targets are known and are recognized as being an essential component of a drug’s biology. However, many other targets fall into the category of “unknown unknowns”. Thus, the collective therapeutic outcome for almost all clinically relevant drugs is reliant on both the claimed primary and secondary “on” targets as well as some of the unexpected unknown “off” targets. This review discusses the biology of several FDA approved cancer therapeutic drugs whose initial reported targets only represented the tip-of-the-iceberg in terms of how each agent acted as an antitumor drug. The review also discusses a putative thorough pre-visualization methodology for drug-based research, prior to executing any wet work. These approaches should be performed in an agnostic fashion and be based in part on the clinically safe drug’s C max and its area under the curve in a patient. Based on tumor heterogeneity, considerations of how to approach developmental therapeutics in the age of “personalized medicine” are also discussed.

Kinase inhibitors: look beyond the label on the bottle